Endogenous opioid peptides are involved in the mediation or modulation of a variety of mammalian physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the effects that have been suggested include analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurological disorders, cardiovascular responses, and respiratory depression (see G. T. Shearman et al. J. Pharmacol. Exp. Ther., 243, 591-597, 1987).
The fact that the effects of endogenous and exogenous opioids are mediated by at least three different types of opioid receptors raises the possibility that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side effects mediated through other opioid receptor types can be minimized or eliminated.
The selectivities of the prototypical delta (naltrindole, U.S. Pat. No. 4,816,586) and kappa (norbinaltorphimine, nor-BNI, U.S. Pat. No. 4,649,200) opioid antagonists have been attributed to the presence of non-peptide xe2x80x9caddress mimicsxe2x80x9d which bear a functional relationship to key motifs in the putative delta and kappa addresses of the endogenous opioid peptides, dynorphin-A and enkephalin, respectively. P. S. Portoghese et al. J. Med. Chem. 1993, 36, 179-180 and U.S. Pat. No. 5,457,208 reported a series of NTI analogues in which the C5xe2x80x2 position of the indolic benzenoid ring is substituted with an alkyl amidine pendant.
Currently a need exists for kappa receptor antagonists that can be used as therapeutic agents, or as pharmacological tools to further investigate kappa receptor binding, structure, and function.
The invention provides a series of kappa antagonists, which demonstrate highly selective pharmacological antagonism both in vivo and in vitro at the kappa opioid receptor.
Accordingly there is provided a compound of the invention which is a compound of formula (I): 
wherein
R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C5-C7)cycloalkenyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C5-C7)cycloalkenyl(C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl;
R2 is H, OH, (C1-C6)alkoxy, (C1-C6)alkanoyloxy, NRaRb or SRc;
R3 is H, aryl(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkylC(xe2x95x90S);
is R4is xe2x95x90O, xe2x95x90S, or xe2x95x90NRd;
Rd is H, CN, CONH2, COCF3, (C1-C6)alkanoyl, (C1-C6)alkyl, or (CH2)pNReRf; or Rd together with R6 is xe2x80x94(CH2)qxe2x80x94 and forms a ring;
p is 1,2,3, or 4;
R5 is NRm;
R6 is H, (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, NRgRh(C1-C6)alkyl, or C(xe2x95x90NRj)NHRk; or when R4 is xe2x95x90NRd, R6 together with Rd is xe2x80x94(CH2)qxe2x80x94 and forms a ring;
q is2 or 3;
X is O, S, or NY;
Y is H, (C1-C6)alkyl, or aryl(C1-C6)alkyl;
n is 0, 1, 2, 3, or 4;
Raxe2x80x94Rc and Rexe2x80x94Rf are each independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or xe2x80x94C(xe2x95x90S)(C1-C6)alkyl;
Rg and Rh are each independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, xe2x80x94C(xe2x95x90NH)NRaRb, or xe2x80x94C(xe2x95x90S)(C1-C6)alkyl, or Rg and Rh together with the nitrogen to which they are attached are pyrrolidino, piperidino or morpholino;
Rj and Rk are each independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C5-C7)cycloalkenylalkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl; and
Rm is hydrogen or (C1-C6)alkyl;
or a pharmaceutically acceptable salt thereof;
The invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
Additionally, the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein kappa receptor activity is implicated and antagonism of kappa receptors is desired comprising administering to the mammal, an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The invention provides a compound of formula I for use in medical therapy (preferably for use in treating conditions wherein antagonism of kappa receptors is indicated, e.g. for appetite suppression, as an antipsychotic, or to treat paralysis due to ischemic spinal cord injury), as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, wherein antagonism of kappa receptors is indicated.
The invention also includes a method for binding a compound of formula I to kappa receptors, in vivo or in vitro, comprising contacting mammalian tissue comprising said receptors with an amount of a compound of formula I effective to bind to said receptors. Tissue comprising ligand bound kappa receptors is useful to measure the receptor selectivity of other potential therapeutic agents, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions wherein kappa receptor activity is implicated and antagonism of kappa receptors is desired, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent (for example in a competitive binding assay).